More Evidence for Chloroquine to Modestly Slow Aging in Rodents

You may recall a recent study in which researchers showed that low dose chloroquine modestly slows aging in rats. Here, an analogous study in mice produces a similar result. This outcome is interesting given that chloroquine inhibits cellular maintenance processes, such as autophagy, that are required for many of the interventions shown to slow aging, such as the practice of calorie restriction. The authors present a range of data on various aspects of mouse biochemistry relevant to aging, but how exactly chloroquine is acting to slow aging, and in ways that outweigh a reduction in normal cellular maintenance, remains up for debate. The prior study pointed to a reduction in cellular senescence and inflammation, but that analysis was not carried out here.

Previous studies have shown that the polyamine spermidine increased the maximum life span in C. elegans and the median life span in mice. Since spermidine increases autophagy, we asked if treatment with chloroquine, an inhibitor of autophagy, would shorten the lifespan of mice. Recently, chloroquine has intensively been discussed as a treatment option for COVID-19 patients. To rule out unfavorable long-term effects on longevity, we examined the effect of chronic treatment with chloroquine given in the drinking water on the lifespan and organ pathology of male middle-aged NMRI mice. We report that, surprisingly, daily treatment with chloroquine extended the median life span by 11.4% and the maximum life span of the middle-aged male NMRI mice by 11.8%.

Subsequent experiments show that the chloroquine-induced lifespan elevation is associated with dose-dependent increase in LC3B-II, a marker of autophagosomes, in the liver and heart that was confirmed by transmission electron microscopy. This supports the hypothesis that long-term treatment led to an accumulation of autophagosomes due to impaired autophagosome fusion with lysosomes. Quite intriguingly, chloroquine treatment was also associated with a decrease in glycogenolysis in the liver suggesting a compensatory mechanism to provide energy to the cell. Accumulation of autophagosomes was paralleled by an inhibition of proteasome-dependent proteolysis in the liver and the heart as well as with decreased serum levels of insulin growth factor binding protein-3 (IGFBP3), a protein associated with longevity. We propose that inhibition of proteasome activity in conjunction with an increased number of autophagosomes and decreased levels of IGFBP3 might play a central role in lifespan extension by chloroquine in male NMRI mice.



From another paper.

"Here, we demonstrate that ATM-centered DNA damage response (DDR) progressively declines with senescence and age, while low dose of chloroquine (CQ) activates ATM, promotes DNA damage clearance, rescues age-related metabolic shift, and prolongs replicative lifespan. Molecularly, ATM phosphorylates SIRT6 deacetylase and thus prevents MDM2-mediated ubiquitination and proteasomal degradation."

Posted by: Lee at June 7th, 2022 4:54 PM
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